Project Summary Anxiety is characterized by anticipation of potential future threats. However, our basic understanding of the neurobiology of attentional and perceptual biases to threat in anxiety is based, not on prestimulus anticipatory response, but on actual neural response to threatening stimuli. These biases are characterized as being driven in a ?bottom-up? manner by threatening stimuli due to their evolutionary salience or physical characteristics. Hence, our knowledge regarding top-down anticipatory factors such as expectations, prior knowledge and contexts in guiding threat perception in anxiety is sparse at best. This stands in stark contrast to substantial basic cognitive neuroscience research demonstrating that top-down prestimulus factors guide perception of threatening and non-threatening stimuli, as well as clinical research showing that anxiety is characterized by inflated expectancies regarding upcoming threats. The overarching goal of this proposal is to bridge this gap in the literature and 1) examine the neural circuitry that implements threat-related top-down biases and its contribution to enhanced perception of threatening stimuli in anxiety and 2) examine whether the neural circuitry implementing top- down and bottom-up contributions to threat perception and their interaction maps on differently to different dimensions of anxiety studied transdiagnostically, thereby establishing the clinical specificity of these measures. Four groups of participants (N=30 each) with a diagnosis of Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder or no anxiety disorder with a range of levels of Anxious Apprehension (AP) and Anxious Arousal (AR) will complete a perceptual decision-making task in which threatening or neutral cues are used to identify subsequently presented fearful and neutral faces. Signal detection measures as well as cue- and stimulus-related brain activity will be recorded via functional magnetic resonance imaging in fusiform face area (FFA), superior temporal sulcus (STS) and amygdala, involved in processing emotional expressions and ventromedial prefrontal cortex involved in maintaining prestimulus representations, to test 3 specific aims. The first aim of this proposal is to delineate the contribution of threat-related cues, as well as prestimulus and stimulus-related neural activity and connectivity in facilitating subsequent perceptual decision making across all participants. The second aim is to determine if enhanced perception and increased prestimulus or stimulus- related neural activity and connectivity due to threat cues is related to AP, even when controlling for AR and diagnostic group status. The final aim is to determine if enhanced perception of threat stimulus (irrespective of cue) and related neural activity and connectivity is associated with AR even when controlling for AP and diagnostic group status. Hence, these aims will establish the specificity of neural measures of top-down and bottom-up aspects of threat perception for AP and AR. Overall, this project will represent an important step in clarifying the neurobiology of anxiety disorders which is predominantly based on prioritized and relatively automatic processing of threatening stimuli. The proposed research will shed light on how prior knowledge about threatening information helps to guide perception in normal and anxious individuals, allowing us to build more comprehensive and ecologically pertinent models in which prior learning, experiences and expectations factor into explaining threat perception in anxiety. Importantly, by examining the differential relationship of prestimulus and stimulus-related neural circuitry with AP and AR transdiagnostically, we hope to uncover potential ways of understanding the structure of anxiety disorders that are not based on traditional DSM diagnostic criteria. Finally, identification of these transdiagnostic affective and neural measures is an important first step towards the development newer treatments for anxiety and improvement of existing treatments that rely on modification of attentional biases.